This invention relates to a method for making pharmaceutical preparations, and more particularly to pharmaceutical preparations having timed-release characteristics.
The maximum time of effectiveness in many pharmaceutical preparations, particularly those containing aspirin as the active analgesic agent, is only a few hours because of biological decomposition of the medication in the body. Consequently, repeated dosages must be taken at frequent intervals to obtain long term pain relief. Furthermore, aspirin usually dissolves readily in the gastric juices of the stomach and the total dosage is immediately fed into the blood stream. The level of the aspirin in the blood stream constantly decreases because of the biological decomposition, so there is little or no pain relief at the end of the period between dosages. As a result, the pain relief fluctuates between dosages corresponding to the peaks and valleys in the level of aspirin in the blood.
Many attempts have been made to develop timed-release pharmaceutical preparations which provide a more constant level of aspirin in the blood over several hours. Generally, three different approaches have been employed to obtain a timed release. In one approach, employing digestion as the release mechanism, the aspirin is either coated or entrapped in a substance which is slowly digested or dispersed into the intestinal tract. The rate of availability of the aspirin is a function of the rate of digestion of the dispersible material. Therefore, the release rate, and thus the analgesic effectiveness of the aspirin, varies from patient to patient depending upon the ability of the patient to digest the material.
In another approach, such as disclosed in U.S. Pat. No. 3,247,066, the aspirin is dispersed in a water-soluble colloid and then coated with a rupturable plastic, non-digestable material which is permeable to the diffusion of water. After ingestion and upon entering the gastrointestinal tract, water in the body fluids diffuses through the coating and causes the colloid to swell. The coating is ruptured by the swelling colloid and the total content of aspirin is released. Although there is substantially less variation in the rate of release from patient to patient, substantially all of the aspirin is released at once resulting in an initially high blood level content which decreases rapidly with time. Also, the additional ingredients and processing steps to disperse the aspirin in the colloid and provide the coating substantially increases the cost of the product.
In another approach commonly referred to as microencapsulation, such as disclosed in U.S. Pat. Nos. 3,488,418, 3,341,416 and 3,155,590, particles of aspirin are first dispersed in a hot solution containing ethyl cellulose and a phase-separation inducing agent, such as butyl rubber or polyethylene. Upon cooling the aspirin particles become coated with ethyl cellulose. The coated particles are then admixed with tabletting excipients and formed into dosage-sized tablets. When ingested, the tablets disintegrate rapidly and the individual particles of encapsulated aspirin are dispersed in the stomach. The gastric juices slowly diffuse through the encapsulant walls, dissolve the aspirin, and the dissolved aspirin slowly diffuses or leaches out through the encapsulant walls into the body. Although the resultant blood level content remains more constant, the aspirin is diffused into the body rapidly enough so there is an initially high blood level content which decreases quite rapidly within a few hours, apparently because of the large surface area contact between the body fluids and the small encapsulated particles. Also, the cost of the additional ingredients and multiple processing steps add to the overall cost of the product.
U.S. Pat. No. 3,115,441 discloses another encapsulation method wherein particles of aspirin are first given a quick thin coating of a film-forming material and a non-toxic, hydrophobic material and are then coated with successive coatings of an organic solvent-resistant material. The coated particles are mixed with uncoated aspirin and this mixture is then formed into a tablet with the coated tablets being entrapped in a matrix of the uncoated aspirin. Tablets made according to this method have the advantage of providing immediate relief because the matrix material (which comprises the initial dosage) dissolves immediately upon ingestion. However, as with the other preparations employing the diffusion technique discussed above, the tablet rapidly disintegrates in the stomach and there is a relatively rapid release of the aspirin. Also, the several coating steps of the process add to the overall cost of the product.